Xanthenecarboxylates, processes for preparing them, and their use as pharmaceutical compositions

ABSTRACT

Xanthenecarboxylates of formula 1  
                 
 
     wherein:  
     A is a group selected from  
                 
 
     X −  is an anion with a single negative charge;  
     R is hydroxy, methyl, hydroxymethyl, ethyl, —CF 3 , —CHF 2 , or fluorine;  
     R 1  and R 2 , which are identical or different, are each C 1 -C 5 -alkyl which is optionally substituted by C 3 -C 6 -cycloalkyl, hydroxy, or halogen, or  
     R 1  and R 2  together denote a —C 3 -C 5 -alkylene-bridge; and  
     R 3 , R 4 , R 3′ , and R 4′ , which are identical or different, are each hydrogen, —C 1 -C 4 -alkyl, —C 1 -C 4 -alkyloxy, hydroxy, —CF 3 , —CHF 2 , —CN, —NO 2 , or halogen,  
     or a physiologically acceptable salt thereof, processes for preparing, them and their use in pharmaceutical compositions.

RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Serial No. 60/368,238, filed Mar. 28, 2002, which is hereby incorporated by reference in its entirety.

SUMMARY OF THE INVENTION

[0002] The present invention relates to new xanthenecarboxylates of general formula 1

[0003] wherein X⁻ and the groups A, R, R¹, R², R³, R^(3′), R⁴, and R^(4′) may have the meanings given in the claims and in the description, processes for preparing them, and their use as pharmaceutical compositions.

BRIEF DESCRIPTIONS OF THE INVENTION

[0004] The present invention relates to compounds of general formula 1

[0005] wherein:

[0006] A denotes a double-bonded group selected from among

[0007] X⁻ an anion with a single negative charge, preferably an anion selected from among chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, andp-toluenesulfonate;

[0008] R denotes hydroxy, methyl, hydroxymethyl, ethyl, —CF₃, —CHF₂, or fluorine;

[0009] R¹ and R², which may be identical or different, denote C₁-C₅-alkyl which may optionally be substituted by C₃-C₆-cycloalkyl, hydroxy, or halogen, or

[0010] R¹ and R² together denote a —C₃-C₅-alkylene-bridge; and

[0011] R³, R⁴, R^(3′), and R^(4′), which may be identical or different, denote hydrogen, —C₁-C₄-alkyl, —C₁-C₄-alkyloxy, hydroxy, —CF₃, —CHF₂, —CN, —NO₂, or halogen.

[0012] Preferred compounds of general formula 1 are those wherein:

[0013] A denotes a double-bonded group selected from among

[0014] X⁻ denotes an anion with a single negative charge selected from among chloride, bromide, 4-toluenesulfonate, and methanesulfonate, preferably bromide;

[0015] R denotes hydroxy, methyl, hydroxymethyl, ethyl, or CHF₂, preferably hydroxy or methyl;

[0016] R¹ and R² which may be identical or different denote methyl, ethyl or fluoroethyl; and

[0017] R³, R⁴, R^(3′), and R^(4′), which may be identical or different, represent hydrogen, methyl, methyloxy, hydroxy, —CF₃, —CHF₂, or fluorine.

[0018] Particularly preferred compounds of general formula 1 are those wherein:

[0019] A denotes a double-bonded group selected from among

[0020] X⁻ denotes an anion with a single negative charge selected from among chloride, bromide, and methanesulfonate, preferably bromide;

[0021] R denotes hydroxy or methyl;

[0022] R¹ and R², which may be identical or different, represent methyl or ethyl, preferably methyl;

[0023] R³, R⁴, R^(3′), and R^(4′), which may be identical or different, represent hydrogen, —CF₃, —CHF₂, or fluorine, preferably hydrogen or fluorine.

[0024] Of particular importance according to the invention are compounds of general formula 1 wherein:

[0025] A denotes a double-bonded group selected from among

[0026] X⁻ denotes bromide;

[0027] R denotes hydroxy or methyl, preferably methyl;

[0028] R¹ and R², which may be identical or different, represent methyl or ethyl, preferably methyl; and

[0029] R³, R⁴, R^(3′), and R^(4′), which may be identical or different, represent hydrogen or fluorine.

[0030] The invention relates to the compounds of formula 1 optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates.

[0031] In the compounds of general formula 1 the groups R³, R⁴, R^(3′), and R^(4′), if they do not represent hydrogen, may in each case be arranged in the ortho, meta, or para position relative to the bond to the “—C—R” group. If none of the groups R³, R⁴, R^(3′), and R^(4′) denotes hydrogen, R³ and R^(3′) are preferably linked in the para position and R⁴ and R^(4′) are preferably linked in the ortho or meta position, most preferably in the meta position. If one of the groups R³ and R⁴ and one of the groups R^(3′) and R^(4′) denotes hydrogen, the other group in each case is preferably bonded in the meta or para position, most preferably in the para position. If none of the groups R³, R⁴, R^(3′), and R^(4′) denotes hydrogen, the compounds of general formula 1 wherein the groups R³, R⁴, R^(3′), and R^(4′) have the same meaning are particularly preferred according to the invention.

[0032] Also of particular importance according to the invention, are those compounds of general formula 1 wherein the ester substituent is in the a configuration on the nitrogen bicyclic group. These compounds correspond to general formula 1-α

[0033] The following compounds are of particular importance according to the invention: tropenol 9-hydroxy-xanthene-9-carboxylate methobromide; scopine 9-hydroxy-xanthene-9-carboxylate methobromide; tropenol 9-methylxanthene-9-carboxylate methobromide; scopine 9-methyl-xanthene-9-carboxylate methobromide; tropenol 9-ethylxanthene-9-carboxylate methobromide; tropenol 9-difluoromethylxanthene-9-carboxylate methobromide; and scopine 9-hydroxymethylxanthene-9-carboxylate methobromide.

[0034] The alkyl groups used, unless otherwise stated, are branched and unbranched alkyl groups having 1 to 5 carbon atoms. Examples include: methyl, ethyl, propyl, or butyl. The groups methyl, ethyl, propyl, or butyl may optionally also be referred to by the abbreviations Me, Et, Prop, or Bu. Unless otherwise stated, the definitions propyl and butyl also include all possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and isopropyl, butyl includes isobutyl, sec-butyl, and tert-butyl, etc.

[0035] The alkylene groups used, unless otherwise stated, are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms. Examples include: methylene, ethylene, propylene, or butylene.

[0036] The alkylene-halogen groups used, unless otherwise stated, are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms which may be mono-, di-, or trisubstituted, preferably disubstituted, by a halogen. Accordingly, unless otherwise stated, the term alkylene-OH groups denotes branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms which may be mono-, di-, or trisubstituted, preferably monosubstituted, by a hydroxy.

[0037] The alkyloxy groups used, unless otherwise stated, are branched and unbranched alkyl groups with 1 to 4 carbon atoms which are linked via an oxygen atom. The following may be mentioned, for example: methyloxy, ethyloxy, propyloxy, or butyloxy. The groups methyloxy, ethyloxy, propyloxy, or butyloxy may optionally also be referred to by the abbreviations MeO, EtO, PropO, or BuO. Unless otherwise stated, the definitions propyloxy and butyloxy also include all possible isomeric forms of the groups in question. Thus, for example, propyloxy includes n-propyloxy and isopropyloxy, butyloxy includes isobutyloxy, sec-butyloxy, and tert-butyloxy, etc. The word alkoxy may also possibly be used within the scope of the present invention instead of the word alkyloxy. The groups methyloxy, ethyloxy, propyloxy, or butyloxy may optionally also be referred to as methoxy, ethoxy, propoxy, or butoxy.

[0038] The alkylene-alkyloxy groups used, unless otherwise stated, are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms which may be mono-, di-, or trisubstituted, preferably monosubstituted, by an alkyloxy group.

[0039] The —O—CO-alkyl groups used, unless otherwise stated, are branched and unbranched alkyl groups with 1 to 4 carbon atoms which are bonded via an ester group. The alkyl groups are bonded directly to the carbonyl carbon of the ester group. The term —O—CO-alkyl-halogen group should be understood analogously. The group —O—CO—CF₃ denotes trifluoroacetate.

[0040] Within the scope of the present invention halogen denotes fluorine, chlorine, bromine, or iodine. Unless otherwise stated, fluorine and bromine are the preferred halogens. The group CO denotes a carbonyl group.

[0041] As explained hereinafter, the compounds according to the invention may be prepared partly analogously to the methods already known in the art (Diagram 1). The carboxylic acid derivatives of formula 3 are known in the art or may be obtained by methods of synthesis known in the art. If only suitably substituted carboxylic acids are known in the art, the compounds of formula 3 may also be obtained directly from them by acid- or base-catalyzed esterification with the corresponding alcohols or by halogenation with the corresponding halogenation reagents.

[0042] As can be seen from Diagram 1, the compounds of formula 2 may be used as starting products for preparing the compounds of formula 1. These compounds are known in the art.

[0043] Starting from the compounds of formula 2 the esters of general formula 4 may be obtained by reaction with the carboxylic acid derivatives of formula 3, wherein R′ denotes, for example, chlorine or a C₁-C₄-alkyloxy group. When R′ is C₁-C₄-alkyloxy, this reaction may be carried out for example in a sodium melt at elevated temperature, preferably at about 50° C.-150° C., more preferably at about 90° C.-100° C. at low pressure, preferably at below 500 mbar, most preferably at below 75 mbar. Alternatively, instead of the derivatives 3 wherein R′ denotes C₁-C₄-alkyloxy, the corresponding acid chlorides (R is Cl) may also be used.

[0044] The compounds of formula 4 thus obtained may be converted into the target compounds of formula 1 by reacting with the compounds R²—X, wherein R² and X may have the abovementioned meanings' This synthesis step may also be carried out analogously to the examples of synthesis disclosed in WO 92/16528. In the case wherein R¹ and R² together form an alkylene bridge, there is no need to add the reagent R²—X, as will be apparent to the skilled man. In this case, the compounds of formula 4 contain a suitably substituted group R¹ (for example —C₃-C₅-alkylene-halogen) according to the above definitions and the compounds of formula 1 are prepared by intramolecular quaternization of the amine.

[0045] Alternatively to the method of synthesizing the compounds of formula 4 shown in Diagram 1, the derivatives 4, wherein the nitrogen bicyclic group denotes a scopine derivative, may be obtained by oxidizing (epoxidizing) compounds of formula 4 wherein the nitrogen bicyclic group is a tropenyl group. According to the invention, the following procedure may be used.

[0046] The compound 4 wherein A denotes —CH═CH— is suspended in a polar organic solvent, preferably in a solvent selected from among N-methyl-2-pyrrolidone (NMP), dimethylacetamide, and dimethylformamide, preferably dimethylformamide and then heated to a temperature of about 30° C.-90° C., preferably 40° C.-70° C. Then a suitable oxidizing agent is added and the mixture is stirred at constant temperature for 2 hours to 8 hours, preferably 3 hours to 6 hours. The oxidizing agent is preferably vanadium pentoxide mixed with H₂O₂, most preferably H₂O₂-urea complex combined with vanadium pentoxide. The mixture is worked up in the usual way. The products may be purified by crystallization or chromatography, depending on their tendency to crystallize.

[0047] Alternatively, the compounds of formula 4 wherein R denotes halogen may also be prepared by the method shown in Diagram 2.

[0048] For this, the compounds of formula 4 wherein R denotes hydroxy are converted into the compounds of formula 4 wherein R denotes halogen using suitable halogenation reagents. The method used for the halogenation reactions to be carried out according to Diagram 2 is sufficiently well known in the art.

[0049] As is apparent from Diagram 1, the intermediate products of general formula 4 have a central importance. Accordingly, in another aspect, the present invention relates to the intermediates of formula 4

[0050] wherein the groups A, R, R¹, R³, R^(3′), R⁴, and R^(4′) may be defined as above, optionally in the form of the acid addition salts thereof.

[0051] By acid addition salts are meant salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulfonate salts, preferably the hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate, and hydromethanesulfonate salts.

[0052] As in the compounds of general formula 1, the groups R³, R⁴, R^(3′), and R^(4′), if they do not represent hydrogen, may in each case be arranged in the ortho, meta, or para position relative to the bond to the “—C—R” group in the compounds of general formula 4 as well. If none of the groups R³, R⁴, R^(3′), and R^(4′) denotes hydrogen, R³ and R^(3′) are preferably linked in the para position and R⁴ and R^(4′) are preferably linked in the ortho or meta position, most preferably in the meta position. If one of the groups R³ and R⁴ and one of the groups R^(3′) and R^(4′) denotes hydrogen, the other group in each case is preferably linked in the meta or para position, most preferably in the para position. If none of the groups R³, R⁴, R^(3′), and R^(4′) denotes hydrogen the compounds of general formula 4 which are particularly preferred according to the invention are those wherein the groups R³, R⁴, R^(3′), and R^(4′) have the same meaning.

[0053] According to the invention, the compounds of formula 4 in the α-configured form are preferably used as the starting materials. These α-configured compounds are therefore of particularly importance according to the invention and correspond to general formula 4-α

[0054] In another aspect, the present invention relates to the use of compounds of general formula 2 for preparing the compounds of general formula 4. Moreover, the present invention relates to the use of the compounds of general formula 2 as starting materials for preparing the compounds of general formula 1. Furthermore, the present invention relates to the use of the compounds of general formula 4 as an intermediate product in the preparation of the compounds of general formula 1.

[0055] The examples of synthesis described below serve to illustrate the present invention still further. However, they are to be regarded as only an example of the procedure, as further illustration of the invention, without restricting the invention to the object described below by way of example.

EXAMPLE 1 Tropenol 9-hydroxyxanthene-9-carboxylate Methobromide

[0056]

[0057] 1.1: Methyl 9-hydroxvxanthene-9-carboxylate 3a

[0058] a) Methyl xanthene-9-carboxylate

[0059] A sodium ethoxide solution is prepared from 21.75 g (0.95 mol) of sodium and 1500 mL of ethanol. 214 g (0.95 mol) of xanthene-9-carboxylic acid is added batchwise to this solution and the suspension obtained is stirred for 1 hour at ambient temperature. Then the solid is separated off, washed with 1500 mL diethyl ether, and the isolated crystals are suspended in 1500 mL of dimethylformamide and combined with 126.73 mL (2.0 mol) of methyl iodide with stirring. The solution formed is left to stand for 24 hours at ambient temperature, then diluted with water to a total volume of 6 L, crystallized, suction filtered, washed with water, and dried. Yield: 167 g of white crystals (74% of theoretical yield); melting point: 82° C.

[0060] b) Methyl 9-hydroxyxanthene-9-carboxylate 3a

[0061] 48.05 g (0.2 mol) methyl xanthene-9-carboxylate are dissolved in 1200 mL of tetrahydrofuran and at 0° C. combined with 23.63 g (0.2 mol) of potassium tert-butoxide. Oxygen is the piped in for 2 hours at −10° C. to −5° C., then the mixture is acidified with 2 N aqueous hydrochloric acid and the majority of the solvent is distilled off. The residue remaining is extracted with ethyl acetate and water, the organic phase is extracted with aqueous Na₂S₂O₅ solution, washed with water, and dried, and the solvent is distilled off. The product is purified by crystallization from diisopropylether and cyclohexane. Yield: 11.10 g white crystals (22% of theoretical yield)

[0062] 1.2: Tropenol 9-hydroxyxanthene-9-carboxylate 4a

[0063] 13.65 g (0.053 mol) of methylester 3a, 8.35 g (0.06 mol) of tropenol and 0.2 g of sodium are heated as a melt at 75 mbar for 4 hours over a bath of boiling water with occasional agitation. After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness, and the residue is extracted with dichloromethane/water. Then the organic phase is washed with water, dried over magnesium sulfate, and the solvent is distilled off. The product is purified by recrystallization from diethyl ether/petroleum ether. Yield: 5.28 g of white crystals (27% of theoretical yield); melting point: 117° C.

[0064] 1.3: Tropenol 9-hvdroxyxanthene-9-carboxylate Methobromide

[0065] 0.8 g (0.002 mol) of 4a are taken up in 20 mL dichloromethane and 20 mL acetonitrile and combined with 1.14 g (0.006 mol) of 50% methylbromide solution in acetonitrile. The reaction mixture is left to stand for 3 days at ambient temperature, during which time the product crystallizes. The crystals precipitated are separated off and recrystallized from acetone to purify them. Yield: 0.94 g of white crystals (93% of theoretical yield); melting point: 249° C.-250° C.; elemental analysis: calculated: C (60.27), H (5.28), N (3.06); found: C (60.04), H (5.34), N (2.98).

EXAMPLE 2 Scopine 9-hydroxyxanthene-9-carboxylate Methobromide

[0066]

[0067] 2.1: Scopine 9-hydroxyxanthene-9-carboxylate 4b

[0068] 6.8 g (0.019 mol) tropenolester 4a are suspended in 75 mL of dimethylformamide and combined with 0.36 g (0.002 mol) of vanadium (V) oxide. At 60° C., a solution of 3.52 g (0.037 mol) of H₂O₂-urea in 15 mL of water is added dropwise and the mixture is stirred for 6 hours at 60° C. After cooling to 20° C., the mixture is adjusted to pH 2 with 4 N hydrochloric acid and combined with Na₂S₂O₅ dissolved in water. The resulting solution is evaporated to dryness and the residue is extracted with dichloromethane/water. The acidic aqueous phase obtained is made basic with Na₂CO₃, extracted with dichloromethane, and the organic phase is dried over Na₂SO₄ and concentrated. Then 1 mL of acetyl chloride are added at ambient temperature and the mixture is stirred for 1 hour. After extraction with 1 N hydrochloric acid, the aqueous phase is made basic, extracted with dichloromethane, and the organic phase is washed with water and dried over magnesium sulfate. Finally, the solvent is distilled off. The crude product is purified by recrystallization from diethyl ether. Yield: 5.7 g of yellow oil (79% of theoretical yield).

[0069] 2.2: Scopine 9-hydroxyxanthene-9-carboxylate Methobromide

[0070] 4.0 g (0.011 mol) of 4b are taken up in 60 mL acetonitrile and reacted with 6.27 g (0.033 mol) of 50% methyl bromide solution in acetonitrile analogously to step 1.3. Yield: 3.6 g of white crystals (69% of theoretical yield); melting point: 226° C.-227° C.; elemental analysis: calculated: C (58.24), H (5.10), N (2.95); found: C (58.33), H (4.98), N (3.05).

EXAMPLE 3 Tropenol 9-methylxanthene-9-carboxylate Methobromide

[0071]

[0072] 3.1.: 9-methylxanthene-9-carboxylic Acid 3b

[0073] a) Methyl 9-methylxanthene-9-carboxylate

[0074] 9.61 g (0.04 mol) of methyl 9-xanthenecarboxylate (obtainable according to step 1.1.a) are dissolved in 150 mL of tetrahydrofuran, combined with a solution of 5.0 g (0.042 mol) potassium lert-butoxide in THF, and stirred for 10 minutes. 5 mL (0.08 mol) of methyl iodide are then added dropwise with gentle cooling; after all has been added, the mixture is stirred for 1 hour at ambient temperature. The reaction mixture is diluted with water to a total volume of 800 mL, extracted with diethyl ether, and the organic phase is extracted with saturated, aqueous Na₂CO₃ solution, washed with water, dried over magnesium sulfate, and the solvent is distilled off. The product is purified by recrystallization from methanol. Yield: 6.05 g of white crystals (70% of theoretical yield); melting point: 91° C.-92° C.

[0075] b) 9-methyl-xanthene-9-carboxylic Acid 3b

[0076] 20.34 g (0.08 mol) of the methyl ester described above and 80 mL of 2 molar aqueous sodium hydroxide solution are stirred in 200 mL dioxane for 24 hours at ambient temperature, then the dioxane is distilled off, the mixture is made up to a total volume of 600 mL with water, extracted with diethyl ether, and the aqueous phase is acidified with 4 N hydrochloric acid. The product crystallizes, is suction filtered, and washed with water; it is purified by recrystallization from acetonitrile. Yield: 14.15 g of white crystals (74% of theoretical yield); melting point: 207° C.-208° C.

[0077] 3.2: tropenol 9-methylxanthene-9-carboxylate 4c

[0078] From 7.76 g (0.03 mol) of 3b, 0.06 mol of oxalyl chloride and 4 drops of dimethylformamide the acid chloride is prepared in 100 mL dichloromethane. It is added dropwise as a solution in dichloromethane to 8.77 g (0.063 mol) of tropenol in 140 mL of dichloromethane, then stirred for 24 hours at 40° C. and cooled. The reaction mixture is extracted with water, dried over magnesium sulfate, and filtered off. The filtrate obtained is acidified to pH 2 with ethereal hydrochloric acid, extracted with diethyl ether, and the aqueous phase is made basic. After extraction with dichloromethane, the organic phase is washed neutral with water, dried over magnesium sulfate, and evaporated to dryness. The residue is dissolved in diethyl ether, insoluble matter is filtered off, and the solvent is removed by distillation. Yield: 3.65 g of yellow oil (34% of theoretical yield).

[0079] 3.3: Tropenol 9-methylxanthene-9-carboxylate Methobromide

[0080] 1.65 g (0.005 mol) of 4c are taken up in 20 mL acetonitrile and reacted with 2.85 g (0.015 mol) of 50% methyl bromide solution in acetonitrile analogously to step 1.3. Yield: 1.5 g of white crystals (65% of theoretical yield); melting point: 212° C.-213° C.; elemental analysis: calculated: C (63.16), H (5.74), N (3.07); found: C (62.50), H (5.94), N (3.11).

EXAMPLE 4 Scopine 9-methylxanthene-9-carboxylate Methobromide

[0081]

[0082] 4.1: Scopine 9-methylxanthene-9-carboxylate 4d

[0083] 1.9 g (0.005 mol) of tropenol ester 4c are suspended in 30 mL of dimethylformamide and reacted with 0.12 g (0.001 mol) of vanadium (V) oxide and 0.01 mol of H₂O₂-urea in water analogously to the method according to step 2.1. Yield: 1.4 g of white crystals (74% of theoretical yield).

[0084] 4.2: Scopine 9-methyl-xanthene-9-carboxylate Methobromide

[0085] 1.35 g (0.004 mol) of 4d are taken up in 10 mL of dichloromethane and 20 mL of acetonitrile and reacted with 2.28 g (0.012 mol) of 50% methyl bromide solution in acetonitrile analogously to step 1.3. Yield: 1.35 g of white crystals (71% of theoretical yield); melting point: 208° C.-209° C.; elemental analysis: calculated: C (61.02), H (5.55), N (2.97); found: C (59.78), H (5.70), N (2.96).

EXAMPLE 5 Tropenol 9-ethylxanthene-9-carboxylate Methobromide

[0086]

[0087] 5.1.: 9-ethylxanthene-9-carboxylic Acid 3c

[0088] a) Methyl 9-ethylxanthene-9-carboxylate

[0089] 10.0 g (0.042 mol) of methyl 9-xanthenecarboxylate (obtainable according to step 1.1.a) are dissolved in 100 mL of tetrahydrofuran and combined batchwise with 5.16 g (0.044 mol) of potassium tert-butoxide while cooling. Then at about 18° C. to 22° C., 6.296 mL (0.083 mol) of bromoethane are added dropwise; after it has all been added, the mixture is stirred for about 1.5 hours at ambient temperature. The precipitate formed is suction filtered and the solvent is removed by distillation. The residue remaining is taken up in diethyl ether and extracted with water. The organic phase is dried over magnesium sulfate and the solvent is removed by distillation. The crude product obtained is used in the next step without any further purification. Yield: 7.92 g of yellow oil (70% of theoretical yield).

[0090] b) 9-ethylxanthene-9-carboxylic Acid 3c

[0091] 7.92 g (0.03 mol) of the ethyl ester described above and 29.5 mL of 2 molar aqueous sodium hydroxide solution are refluxed in 80 mL dioxane for 2.5 hours. The mixture is worked up as in step 3.1.b). Yield: 4.46 g of white crystals (58% of theoretical yield); melting point: 175° C.-176° C.

[0092] 5.2: Tropenol 9-ethylxanthene-9-carboxylate 4e

[0093] From 4.46 g (0.03 mol) of 3c, 4.45 g (0.035 mol) of oxalyl chloride and 3 drops of dimethylformamide the acid chloride is prepared in 40 mL of dichloromethane. It is added as a solution in dichloromethane to 4.87 g (0.035 mol) of tropenol in 60 mL of dichloromethane and reacted analogously to the procedure according to step 3.2 and worked up. Yield: 0.97 g of oil (15% of theoretical yield).

[0094] 5.3: Tropenol 9-ethylxanthene-9-carboxylate Methobromide

[0095] 0.97 g (0.003 mol) of 4e are taken up in 70 mL acetonitrile and reacted with 1.77 g (0.009 mol) of 50% methyl bromide solution in acetonitrile analogously to Step 1.3. To purify it, the product is recrystallized from acetonitrile. Yield: 0.65 g white crystals (46% of theoretical yield); melting point: 217° C.-218° C.; elemental analysis: calculated: C (63.83), H (6.00), N (2.98); found: C (61.76), H (6.32), N (2.92).

EXAMPLE 6 Tropenol 9-difluoromethyl-xanthene-9-carboxylate Methobromide

[0096]

[0097] 6.1.: 9-difluoromethyl-xanthene-9-carboxylic Acid 3d

[0098] a) Methyl 9-difluoromethyl-xanthene-9-carboxylate

[0099] 16.8 g (0.07 mol) of methyl 9-xanthenecarboxylate (obtainable according to step 1.1.a) are dissolved in 300 mL of tetrahydrofuran and 9.1 g (0.077 mol) of potassium tert-butoxide are added batchwise while cooling. Then difluorochloromethane is piped in at 0° C. over a period of 1.5 hours. After all the gas has been piped in, the reaction mixture is left to stand for 72 hours at ambient temperature. The reaction mixture is then diluted with water to a total volume of about 2000 mL, extracted with ethyl acetate, the organic phase is separated off and washed with 5% aqueous sodium carbonate solution. After being extracted again with water, the organic phase is dried over magnesium sulfate and the solvent is removed by distillation. The crude product is purified by chromatography on silica gel (eluent: cyclohexane-ethyl acetate (98:2)) or by recrystallization from cyclohexane. Yield: 5.35 g of white crystals (26% of theoretical yield); melting point: 101° C.

[0100] b) 9-difluoromethylxanthene-9-carboxylic Acid 3d

[0101] 5.38 g (0.019 mol) of the ester described above and 18.5 mL of 2 molar aqueous sodium hydroxide solution are reacted in 60 mL of dioxane and worked up analogously to the reaction in Step 3.1.b). Yield: 2.77 g white crystals (53% of theoretical yield); melting point: 181° C.-182° C.

[0102] 6.2: 9-difluoromethylxanthene-9-carboxylate Tropenol 4f

[0103] From 2.77 g (0.01 mol) of 3d, 1 mL of oxalyl chloride and 1 drop of dimethylformamide the acid chloride is prepared. It is added to 2.78 g (0.02 mol) of tropenol in 50 mL of 1,2-dichloroethane and reacted and worked up analogously to step 3.2. Yield: 0.6 g of oil (15% of theoretical yield).

[0104] 6.3: Tropenol 9-difluoromethyl-xanthene-9-carboxylate Methobromide

[0105] 0.6 g (0.002 mol) 4f are taken up in 20 mL acetonitrile and reacted with 1.14 g (0.006 mol) of 50% methyl bromide solution in acetonitrile analogously to step 1.3. Yield: 0.44 g beige crystals (45% of theoretical yield); melting point: 227° C.-228° C.; elemental analysis: calculated: C (58.55), H (4.91), N (2.84); found: C (57.19), H (5.11), N (2.86).

EXAMPLE 7 Scopine 9-hydroxymethylxanthene-9-carboxylate Methobromide

[0106]

[0107] 7.1.: Scopine 9-hydroxymethylxanthene-9-carboxylate 4g

[0108] 3.63 g (0.010 mol) of scopine xanthene-9-carboxylate, which may be obtained as described in WO 92/16528, are dissolved in 20 mL of dimethylformamide and combined with 0.36 g (0.012 mol) of paraformaldehyde. After the addition of 0.168 g (0.002 mol) of potassium tert-butoxide at 20° C., the mixture is stirred for 2 hours at ambient temperature. The mixture is acidified to pH 2 with 4 N hydrochloric acid with cooling and the solvent is distilled off in vacuo. The residue remaining is extracted with diethyl ether and water, and the aqueous phase is made basic with 10% sodium carbonate solution and extracted with dichloromethane. The organic phase is separated off and washed with water, dried, and the solvent is distilled off in vacuo. To purify it, the product is recrystallized from acetonitrile. Yield: 1.55 g white crystals (36% of theoretical yield); melting point: 232° C.

[0109] 7.2: Scopine 9-hydroxymethylxanthene-9-carboxylate Methobromide

[0110] 1.15 g (0.003 mol) of 4g are taken up in 20 mL acetonitrile and reacted with 1.71 g (0.009 mol) of 50% methyl bromide solution in acetonitrile analogously to step 1.3. Yield: 1.28 g of white crystals (87% of theoretical yield); melting point: 234° C.; elemental analysis: calculated: C (59.02), H (5.37), N (2.87); found: C (59.30), H (5.41), N (3.03).

[0111] It was found that the compounds according to the invention of formula 1 are antagonists of the M3 receptor (Muscarinic Receptor subtype 3). The compounds according to the invention have K_(i) values of less than 10 nM in terms of their affinity for the M3 receptor. These values were determined by the method described below.

[0112] Chemicals

[0113]³H-NMS was obtained from Messrs. Amersham of Braunschweig, with a specific radioactivity of 3071 GBq/mmol (83 Ci/mmol). All the other reagents were obtained from Serva of Heidelberg and Merck of Darmstadt.

[0114] Cell Membranes

[0115] We used cell membranes from CHO (Chinese hamster ovary) cells which were transfected with the corresponding genes of the human muscarinic receptor subtypes hml to hm5 (BONNER). The cell membranes of the desired subtype were thawed, resuspended by hand with a glass homogenizer and diluted with HEPES buffer to a final concentration of 20-30 mg of protein/mL.

[0116] Receptor Binding Studies

[0117] The binding assay was carried out in a final volume of 1 mL and consisted of 100 μL of unlabelled substance in various concentrations, 100 μL of radioligand (3H—N-methylscopolamine 2 nmol/L (³H-NMS), 200 μL of membrane preparation and 600 μl of HEPES buffer (20 mmol/L HEPES, 10 mmol/L MgCl₂, 100 mmol/L NaCl, adjusted with 1 mol/L NaOH to pH 7.4).

[0118] The nonspecific binding was determined using 10 μmol/L of atropine. The preparation was incubated for 45 minutes at 37° C. in 96-well microtitre plates (Beckman, polystyrene, No. 267001) as a double measurement. The incubation was ended by filtering using an Inotech Cell Harvester (type IH 110) through Whatman G-7 filters. The filters were washed with 3 mL of ice-cooled HEPES buffer and dried before measuring.

[0119] Determining the Radioactivity

[0120] The radioactivity of the filter mats was measured simultaneously using a two-dimensional digital autoradiograph (Berthold, Wildbad, type 3052).

[0121] Evaluation

[0122] The K_(i) values were calculated using implicit equations which were derived directly from the mass-action law, with the model for the 1 receptor 2 ligand reaction (SysFit—Software, SCHITTKOWSKI).

[0123] Literature

[0124] BONNER TI, New Subtypes of Muscarinic Acetylcholine Receptors, Trends Pharmacol. Sci. 10, Suppl.: 11-15 (1989); SCHITTKOWSKI K, Parameter Estimation in Systems of Nonlinear Equations, Numer Math. 68: 129-142 (1994).

[0125] The compounds of formula 1 according to the invention are characterized by their range of uses in the therapeutic field. Particular mention should be made of those applications for which the compounds of formula 1 according to the invention may preferably be used on the basis of their pharmaceutical activity as anticholinergics.

[0126] These are for example the treatment of asthma chronic obstructive pulmonary disease (COPD). The compounds of general formula 1 may also be used to treat vagally induced sinus bradycardia and to treat heart rhythm disorders. Generally, the compounds according to the invention may also be used therapeutically to treat spasms, for example, in the gastrointestinal tract. They may also be used to treat spasms in the urinary tract and also to treat menstrual pain, for example. Of the ranges of indications mentioned above, the treatment of asthma and COPD with the compounds of formula 1 according to the invention is of particular importance.

[0127] The compounds of general formula 1 may be used on their own or in conjunction with other active substances of formula 1. The compounds of general formula 1 may also be used in combination with other pharmacologically active substances. These may be, in particular, betamimetics, antiallergics, PAF antagonists, PDE IV inhibitors, leukotriene antagonists, p38 kinase inhibitors, EGFR-kinase inhibitors, and corticosteroids, as well as combinations of these active substances.

[0128] Examples of betamimetics which may be used according to the invention in conjunction with the compounds of formula 1 include compounds selected from among bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulfonterol, terbutaline, tolubuterol, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluormethylphenyl)-2-tert-butylamino)ethanol, and 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol, optionally in the form of the racemates, the enantiomers, the diastereomers, and optionally the pharmacologically acceptable acid addition salts thereof, the solvates, and/or the hydrates thereof. Most preferably, the betamimetics used as active substances in conjunction with the compounds of formula 1 according to the invention are selected from among fenoterol, formoterol, salmeterol, 1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, optionally in the form of the racemates, the enantiomers, the diastereomers, and optionally the pharmacologically acceptable acid addition salts thereof, and/or the hydrates thereof. Of the betamimetics mentioned above the compounds formoterol and salmeterol are particularly preferred, optionally in the form of the racemates, the enantiomers, the diastereomers, and optionally the pharmacologically acceptable acid addition salts thereof, and the hydrates thereof. According to the invention, the acid addition salts of the betamimetics selected, for example, from among the hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate, and xinafoate are preferred. Particularly preferred in the case of salmeterol are the salts selected from among the hydrochloride, sulfate, and xinafoate, of which the xinafoate is particularly preferred. Particularly preferred in the case of formoterol are the salts selected from among the hydrochloride, sulfate, and fumarate, of which the hydrochloride and fumarate are particularly preferred. According to the invention, formoterol fumarate is of exceptional importance.

[0129] Within the scope of the present invention, the corticosteroids which may optionally be used in conjunction with the compounds of formula 1 may be compounds selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW 215864, KSR 592, ST-126, and dexamethasone. Preferably, within the scope of the present invention, the corticosteroids are selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, and dexamethasone, while budesonide, fluticasone, mometasone, and ciclesonide are important and budesonide and fluticasone are particularly important. In some cases, within the scope of the present patent application, the term steroids is used on its own instead of the word corticosteroids. Any reference to steroids within the scope of the present invention includes a reference to salts or derivatives which may be formed from the steroids. Examples of possible salts or derivatives include: sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates, or furoates. In some cases, the corticosteroids may also occur in the form of their hydrates.

[0130] Examples of PDE-IV inhibitors which may be used according to the invention in combination with the compound of formula 1 include compounds selected from among enprofylline, roflumilast, ariflo, Bay-198004, CP-325,366, BY343, D-4396 (Sch-351591), V-11294A, and AWD-12-281. Preferred PDE-IV inhibitors are selected from among enprofylline, roflumilast, ariflo, and AWD-12-281, while AWD-12-281 is particularly preferred for combining with the compounds of formula 1 according to the invention. Any reference to the abovementioned PDE-IV inhibitors also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts thereof which may exist. By the physiologically acceptable acid addition salts which may be formed by the abovementioned PDE-IV inhibitors are meant, for example, pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, and maleic acid. According to the invention, the salts selected from among the acetate, hydrochloride, hydrobromide, sulfate, phosphate, and methanesulfonate salts are preferred.

[0131] Within the scope of the present invention, the term dopamine agonists, which may optionally be used in conjunction with the compounds of formula 1, denotes compounds selected from among bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindole, ropinirole, talipexole, terguride, and viozan. It is preferable within the scope of the present invention to use, as combination partners with the compounds of formula 1, dopamine agonists selected from among pramipexol, talipexole and viozan, pramipexol being of particular importance. Any reference to the abovementioned dopamine agonists also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts and hydrates thereof which may exist. By the physiologically acceptable acid addition salts thereof which may be formed by the abovementioned dopamine agonists are meant, for example, pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, and maleic acid.

[0132] Examples of antiallergic agents which may be used according to the invention as a combination with the compound of formula 1 include epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifene, emedastine, dimetindene, clemastine, bamipine, hexachloropheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratadine, and meclizine. Preferred antiallergic agents which may be used within the scope of the present invention in combination with the compounds of formula 1 according to the invention are selected from among epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, ebastine, desloratadine and mizolastine, epinastine, and desloratadine being particularly preferred. Any reference to the abovementioned antiallergic agents also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts thereof which may exist.

[0133] Examples of PAF antagonists which may be used according to the invention as a combination with the compounds of formula 1 include 4-(2-chlorophenyl)-9-methyl-2-[3 (4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine and 6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclopenta[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]d iazepine.

[0134] Especially preferred examples of EGFR-kinase inhibitors which may be used according to the invention as a combination with the compounds of formula 1 include, in particular, 4-[(3-chloro-4-fluorophenyl)amino]-7-[4-((R)-6-methyl-2-oxomorpholin-4-yl)butyloxy]-6-[(vinylcarbonyl)amino]quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[4-((S)-6-methyl-2-oxomorpholin-4-yl)butyloxy]-6-[(vinylcarbonyl)amino]quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-(2-{4-[(S)-(2-oxotetrahydrofuran-5-yl)carbonyl]piperazin-1-yl}ethoxy)-6-[(vinylcarbonyl)amino]quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-((S)-6-methyl-2-oxomorpholin-4-yl)ethoxy]-6-[(vinylcarbonyl)amino]quinazoline, 4-[(3-chloro4-fluorophenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)ethyl]-N-[(ethoxycarbonyl)methyl]amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline, 4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]-amino}-7-cyclopropylmethoxyquinazoline, and 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(morpholin-4-yl)propyloxy]-7-methoxyquinazoline. Any reference to the abovementioned EGFR-kinase inhibitors also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts thereof which may exist. By the physiologically or pharmacologically acceptable acid addition salts thereof which may be formed by the EGFR-kinase inhibitors are meant, for example, pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, and maleic acid. According to the invention, the salts of the EGFR-kinase inhibitors selected from among the salts of acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and methanesulfonic acid are preferred.

[0135] Particularly preferred examples of p38 kinase inhibitors which may be used according to the invention as a combination with the compounds of formula 1 include, in particular, 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalin-1-yl]urea, 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxothiomorpholin-4-yl)ethoxy)naphthalin-1-yl]urea, 1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridine-4-ylethoxy)naphthalin-1-yl]urea, 1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalin-1-yl]urea, or 1-[5-tertbutyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea. Any reference to the abovementioned p38-kinase inhibitors also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts thereof which may exist. By the physiologically or pharmacologically acceptable acid addition salts thereof which may be formed by the p38 kinase inhibitors are meant, for example, pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, and maleic acid.

[0136] If the compounds of formula 1 are used in conjunction with other active substances, the combination with steroids, PDE IV inhibitors, or betamimetics is particularly preferred, of the categories of compounds mentioned above. The combination with betamimetics, particularly with long-acting betamimetics, is of particular importance. The combination of the compounds of formula 1 according to the invention with salmeterol or formoterol is particularly preferred.

[0137] Suitable preparations for administering the salts of formula 1 include for example tablets, capsules, suppositories and solutions, etc. Administration of the compounds according to the invention by inhalation is of particular importance according to the invention (particularly for treating asthma or COPD). The content of the pharmaceutically active compound(s) should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-% of the composition as a whole. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.

[0138] Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

[0139] Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavor enhancer, e.g., a flavoring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

[0140] Solutions are prepared in the usual way, e.g., with the addition of isotonic agents, preservatives such as p-hydroxybenzoates or stabilizers such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and/or dispersants, while if water is used as diluent, for example, organic solvents may optionally be used as solubilizers or dissolving aids, and the solutions may be transferred into injection vials or ampoules or infusion bottles.

[0141] Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.

[0142] Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.

[0143] Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), vegetable oils (e.g., groundnut or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerol), carriers such as, e.g., natural mineral powders (e.g., kaolins, clays, talc, and chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), sugars (e.g., cane sugar, lactose, and glucose), emulsifiers (e.g., lignin, spent sulfite liquors, methylcellulose, starch, and polyvinylpyrrolidone) and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).

[0144] For oral use, the tablets may obviously contain, in addition to the carriers specified, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additional substances such as starch, preferably potato starch, gelatin and the like. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc may also be used to produce the tablets. In the case of aqueous suspensions, the active substances may be combined with various flavor enhancers or colorings in addition to the abovementioned excipients.

[0145] When the compounds of formula 1 are used for the treatment of asthma or COPD, they are preferably administered as preparations or pharmaceutical formulations for inhalation. For inhalation, the compounds may be in the form of inhalable powders propellant-containing metering aerosols, or propellant-free inhalable solutions. Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile inhalable solutions ready for use. The formulations which may be used within the scope of the present invention are described in detail in the next part of the specification.

[0146] The inhalable powders which may be used according to the invention may contain the compounds of formula 1 either on their own or in admixture with suitable physiologically acceptable excipients. If the active substances 1 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention: monosaccharides (e.g., glucose or arabinose), disaccharides (e.g., lactose, saccharose, or maltose), oligo- and polysaccharides (e.g., dextrane), polyalcohols (e.g., sorbitol, mannitol, or xylitol), salts (e.g., sodium chloride or calcium carbonate) or mixtures of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.

[0147] Within the scope of the inhalable powders according to the invention, the excipients have a maximum average particle size of up to 250 μm, preferably between 10 μm and 150 μm, most preferably between 15 μm and 80 μm. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of 1 μm to 9 μm to the excipients mentioned above. These finer excipients are also selected from the group of possible excipients listed hereinbefore. Finally, in order to prepare the inhalable powders according to the invention, micronised active substance 1, preferably with an average particle size of 0.5 μm to 10 μm, more preferably from 1 μm to 5 μm, is added to the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronizing and by finally mixing the ingredients together are known from the prior art. The inhalable powders according to the invention may be administered using inhalers known from the prior art.

[0148] The inhalation aerosols containing propellant gas which may be used according to the invention, may contain the compounds of formula 1 dissolved in the propellant gas or in dispersed form. The compounds of formula 1 may be present in separate preparations or in a combined preparation, while the compounds of formula 1 may either both be dissolved, both dispersed, or only one component is dissolved and the other may be dispersed.

[0149] The propellant gases which may be used to prepare the inhalation aerosols are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane, or isobutane and halohydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane, or cyclobutane. The propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a and TG227 and mixtures thereof.

[0150] The propellant-driven inhalation aerosols may also contain other ingredients such as cosolvents, stabilizers, surfactants, antioxidants, lubricants, and pH adjusters. All these ingredients are known in the art.

[0151] The propellant-driven inhalation aerosols mentioned above may be administered using inhalers known in the art such as metered dose inhalers (MDIs).

[0152] Moreover, the active substances 1 according to the invention may be administered in the form of propellant-free inhalable solutions and suspensions. The solvent used may be an aqueous or alcoholic, preferably an ethanolic solution. The solvent may be water on its own or a mixture of water and ethanol. The relative proportion of ethanol compared with water is not limited but the maximum is up to 70 percent by volume, more particularly up to 60 percent by volume, and most preferably up to 30 percent by volume. The remainder of the volume is made up of water. The solutions or suspensions containing compounds of formula 1 are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid, and/or propionic acid. Preferred inorganic acids are hydrochloric and sulfuric acids. It is also possible to use the acids which already form an acid addition salt. Of the organic acids, ascorbic acid, fumaric acid, and citric acid are preferred. If desired, mixtures of the above acids may be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g., as flavorings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.

[0153] In these formulations it may be possible to do without the addition of edetic acid (EDTA) or one of the known salts thereof, sodium edetate, as stabilizer or complexing agent. Other embodiments would contain one or more of these compounds. In a preferred embodiment the content, based on sodium edetate, is less than 100 mg/100 mL, preferably less than 50 mg/100 mL, most preferably less than 20 mg/100 mL. Generally, inhalable solutions in which the content of sodium edetate is from 0 to 10 mg/100 mL are preferred. Cosolvents and/or other excipients may be added to the propellant-free inhalable solutions. Preferred cosolvents are thus those which contain hydroxyl groups or other polar groups, such as alcohols, particularly isopropyl alcohol; glycols, particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycol ether; glycerol; polyoxyethylene alcohols; and polyoxyethylene fatty acid esters. By excipients and additives are meant, in this context, any pharmacologically acceptable substance which is not an active substance, but can be formulated together with the active substance(s) in the pharmacologically suitable solvent to improve the qualitative properties of the active substance formulation. Preferably, these substances have no noticeable or at least no unwanted pharmacological activity in the context of the desired therapy. The excipients and additives include, e.g., surfactants such as soya lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants, and/or preservatives which guarantee or extend the shelf life of the finished pharmaceutical formulation, flavorings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as, for example, sodium chloride, as isotonic agents.

[0154] The preferred excipients include antioxidants, such as, for example, ascorbic acid, unless already used to adjust the pH, vitamin A, vitamin E, tocopherols, and similar vitamins or provitamins which occur in the human body.

[0155] Preservatives may be used to protect the formulation from contamination with pathogens. Suitable preservatives are those known in the art, particularly cetylpyridinium chloride, benzalkonium chloride, or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. The abovementioned preservatives are preferably present in concentrations of up to 50 mg/100 mL, most preferably between 5 mg/100 mL and 20 mg/100 mL. Preferred formulations contain only benzalkonium chloride and sodium edetate, in addition to the solvent water and the active substance 1. In another preferred embodiment, no sodium edetate is used.

[0156] The dosage of the compounds according to the invention is naturally highly dependent on the method of administration and the complaint which is being treated. When administered by inhalation the compounds of formula 1 are characterized by a high potency even at doses in the μg range. The compounds of formula 1 may also be used effectively above the μg range. The dosage may then be in the gram range, for example. When administered by routes other than by inhalation the compounds according to the invention may be administered in higher doses (for example, but not restrictively, in the range from 1 to 1000 mg).

[0157] The following examples of formulations illustrate the present invention without restricting its scope:

[0158] Examples of Pharmaceutical Formulations A. Tablets Containing 100 mg of Active Substance Component Amount per tablet (mg) active substance 1 100 lactose 140 corn starch 240 polyvinylpyrrolidone 15 magnesium stearate 5 TOTAL 500

[0159] The finely ground active substance, lactose, and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated, and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size. Component Amount per tablet (mg) active substance 1 80 lactose 55 corn starch 190 microcrystalline cellulose 35 polyvinylpyrrolidone 15 sodium-carboxymethyl starch 23 magnesium stearate 2 TOTAL 400

[0160] The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose, and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodium carboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size. C. Ampoule Solution Containing 50 mg of Active Substance Component Amount active substance 1 50.0 mg sodium chloride   50 mg water for inj.   5 mL

[0161] The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make the solution isotonic. The resulting solution is filtered to remove pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilized and heat-sealed. The ampoules contain 5 mg, 25 mg and 50 mg of active substance. D. Metering Aerosol Component Amount active substance 1 0.005 sorbitan trioleate 0.1 monofluorotrichloromethane and ad 100 difluorodichloromethane (2:3)

[0162] The suspension is transferred into a conventional aerosol container with metering valve. Preferably 50 μL suspension are released on each actuation. The active substance may 5 also be released in higher doses if desired (e.g., 0.02 wt.-%). E. Solution Component mg/100 mL active substance 1 333.3 formoterol fumarate 333.3 benzalkonium chloride 10.0 EDTA 50.0 HCl (1 N) to pH 3.4

[0163] This solution may be prepared in the usual way. F. Inhalable Powder Component Amount active substance 1 6 μg formoterol fumarate 6 μg lactose monohydrate to 25 mg

[0164] The inhalable powder is prepared in the usual way by mixing the individual ingredients. G. Inhalable Powder Component Amount active substance 1 10 μg lactose monohydrate to 25 mg

[0165] The inhalable powder is prepared in the usual way by mixing the individual ingredients. 

We claim:
 1. A compound of formula 1

wherein: A is a group selected from

X⁻ is an anion with a single negative charge; R is hydroxy, methyl, hydroxymethyl, ethyl, —CF₃, —CHF₂, or fluorine; R¹ and R², which are identical or different, are each C₁-C₅-alkyl which is optionally substituted by C₃-C₆-cycloalkyl, hydroxy, or halogen, or R¹ and R² together denote a —C₃-C₅-alkylene-bridge; and R³, R⁴, R^(3′), and R^(4′), which are identical or different, are each hydrogen, —C₁-C₄-alkyl, —C₁-C₄-alkyloxy, hydroxy, —CF₃, —CHF₂, —CN, —NO₂, or halogen, or a physiologically acceptable salt thereof.
 2. The compound of general formula 1 according to claim 1, wherein: A is a group selected from

X⁻ is an anion with a single negative charge selected from chloride, bromide, 4-toluenesulfonate, and methanesulfonate; R is hydroxy, methyl, hydroxymethyl, ethyl, or CHF₂; R¹ and R², which are identical or different, are each methyl, ethyl, or fluoroethyl; and R³, R⁴, R^(3′), and R^(4′), which are identical or different, are each hydrogen, methyl, methyloxy, hydroxy, —CF₃, —CHF₂, or fluorine, or a physiologically acceptable salt thereof.
 3. The compounds of formula 1 according to claim 1, wherein: A is a group selected from

X⁻ is an anion with a single negative charge selected from chloride, bromide, and methanesulfonate; R is hydroxy or methyl; R¹ and R², which are identical or different, are each methyl or ethyl; and R³, R⁴, R^(3′), and R^(4′), which are identical or different, are each hydrogen, —CF₃, —CHF₂, or fluorine, or a physiologically acceptable salt thereof.
 4. The compound of formula 1 according to claim 1, wherein: A is a group selected from

X⁻ is bromide; R is hydroxy or methyl; R¹ and R², which are identical or different, are each methyl or ethyl; and R³, R⁴, R^(3′), and R^(4′), which are identical or different, are each hydrogen or fluorine, or a physiologically acceptable salt thereof.
 5. The compound of formula 1 according to claim 1, wherein: A is a group selected from

X⁻ is bromide; R is methyl; R¹ and R² are each methyl; and R³, R⁴, R^(3′), and R^(4′), which are identical or different, are each hydrogen or fluorine, or a physiologically acceptable salt thereof.
 6. A pharmaceutical composition comprising an effective amount of a compound of formula 1 according to claim 1 or a physiologically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier.
 7. A pharmaceutical composition comprising an effective amount of a compound of formula 1 according to claim 2 or a physiologically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier.
 8. A pharmaceutical composition comprising an effective amount of a compound of formula 1 according to claim 3 or a physiologically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier.
 9. A pharmaceutical composition comprising an effective amount of a compound of formula 1 according to claim 4 or a physiologically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier.
 10. A pharmaceutical composition comprising an effective amount of a compound of formula 1 according to claim 5 or a physiologically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier.
 11. A pharmaceutical composition according to claim 6, further comprising an additional active substance selected from betamimetics, antiallergics, PAF antagonists, PDE-IV inhibitors, leukotriene antagonists, p38 kinase inhibitors, EGFR kinase inhibitors, and corticosteroids.
 12. A pharmaceutical composition according to claim 7, further comprising an additional active substance selected from betamimetics, antiallergics, PAF antagonists, PDE-IV inhibitors, leukotriene antagonists, p38 kinase inhibitors, EGFR kinase inhibitors, and corticosteroids.
 13. A pharmaceutical composition according to claim 8, further comprising an additional active substance selected from betamimetics, antiallergics, PAF antagonists, PDE-IV inhibitors, leukotriene antagonists, p38 kinase inhibitors, EGFR kinase inhibitors, and corticosteroids.
 14. A pharmaceutical composition according to claim 9, further comprising an additional active substance selected from betamimetics, antiallergics, PAF antagonists, PDE-IV inhibitors, leukotriene antagonists, p38 kinase inhibitors, EGFR kinase inhibitors, and corticosteroids.
 15. A pharmaceutical composition according to claim 10, further comprising an additional active substance selected from betamimetics, antiallergics, PAF antagonists, PDE-IV inhibitors, leukotriene antagonists, p38 kinase inhibitors, EGFR kinase inhibitors, and corticosteroids.
 16. A method for treatment of a disease that benefits from treatment with anticholinergics in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of formula 1 according to claim
 1. 17. A method for treatment of a disease that benefits from treatment with anticholinergics in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of formula 1 according to claim
 2. 18. A method for treatment of a disease that benefits from treatment with anticholinergics in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of formula 1 according to claim
 3. 19. A method for treatment of a disease that benefits from treatment with anticholinergics in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of formula 1 according to claim
 4. 20. A method for treatment of a disease that benefits from treatment with anticholinergics in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of formula 1 according to claim
 5. 21. A method for treatment of a disease selected from asthma, COPD, vagally induced sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract, spasms in the urinary tract, and menstrual pain, in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of formula 1 according to claim
 1. 22. A method for treatment of a disease selected from asthma, COPD, vagally induced sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract, spasms in the urinary tract, and menstrual pain, in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of formula 1 according to claim
 2. 23. A method for treatment of a disease selected from asthma, COPD, vagally induced sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract, spasms in the urinary tract, and menstrual pain, in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of formula 1 according to claim
 3. 24. A method for treatment of a disease selected from asthma, COPD, vagally induced sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract, spasms in the urinary tract, and menstrual pain, in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of formula 1 according to claim
 4. 25. A method for treatment of a disease selected from asthma, COPD, vagally induced sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract, spasms in the urinary tract, and menstrual pain, in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of formula 1 according to claim
 5. 26. A compound of formula 4

wherein: A is a group selected from

R is hydroxy, methyl, hydroxymethyl, ethyl, —CF₃, —CHF₂, or fluorine; R¹ and R², which are identical or different, are each C₁-C₅-alkyl which is optionally substituted by C₃-C₆-cycloalkyl, hydroxy, or halogen, or R¹ and R² together denote a —C₃-C₅-alkylene-bridge; and R³, R⁴, R^(3′), and R^(4′), which are identical or different, are each hydrogen, —C₁-C₄-alkyl, —C₁-C₄-alkyloxy, hydroxy, —CF₃, —CHF₂, —CN, —NO₂, or halogen, or an acid addition salt thereof. 